Electrocardiographic patterns of superior right ventricular outflow tract tachycardias: distinguishing septal and free-wall sites of origin

INTRODUCTION: The superior right ventricular outflow tract (RVOT) septum and free wall are common locations of origin for outflow tract ventricular tachycardias (VT). We hypothesized that (1) unique ECG morphologies of pace maps from septal and free-wall sites in the superior RVOT could be identified using magnetic electroanatomic mapping for accurate anatomical localization; and (2) this ECG information could help facilitate pace mapping and accurate VT localization. METHODS AND RESULTS: In 14 patients with structurally normal hearts who were undergoing ablation for outflow tract VT, a detailed magnetic electroanatomic map of RVOT was constructed in sinus rhythm, then pace mapping was performed from anterior, mid, and posterior sites along the septum and free wall of the superior RVOT. Pace maps were analyzed for ECG morphologies in limb leads and transition patterns in precordial leads. Monophasic R waves in inferior leads for septal sites were taller (1.7 +/- 0.4 mV vs 1.1 +/- 0.3 mV; P < 0.01) and narrower (158 +/- 21 msec vs 168 +/- 15 msec; P < 0.01) compared with free-wall sites; lacked "notching" (28.6% vs 95.2%; P < 0.05); and showed early precordial transition (by lead V4; 78.6% vs 4.8%; P < 0.05). A positive R wave in lead I also distinguished posterior from anterior septal and free-wall sites. Based on QRS morphology in limb leads and precordial transition pattern (early vs late), in a retrospective analysis, a blinded reviewer was able to accurately localize the site of origin of clinical arrhythmia (the successful ablation site on the magnetic electroanatomic map) in 25 of 28 patients (90%) with superior RVOT VT. CONCLUSION: Pace maps in the superior RVOT region manifest site-dependent ECG morphologies that can help in differentiating free-wall from septal locations and posterior from anterior locations. Despite overlap in QRS amplitude and duration, in the majority of patients a combination of ECG features can serve as a useful template in predicting accurately the site of origin of clinical arrhythmias arising from this region.     

Lipoprotein(a) as an independent risk factor for coronary artery disease in patients below 40 years of age

Coronary artery disease has assumed alarming proportions in Indians and often affects people at younger age. Traditional risk factors fail to explain the high incidence of disease. Although lipoprotein(a) has been shown to be a powerful risk factor for atherosclerosis, there is very limited data with regard to its significance in premature coronary artery disease. The present study was therefore undertaken to assess lipoprotein(a) levels and its role as a marker of coronary artery disease in patients below the age of 40 years. Lipid profile and lipoprotein(a) levels were estimated in 50 patients of angiographically proven coronary artery disease and an equal number of age-matched healthy controls. There was no significant difference in the family history of coronary artery disease, body mass index and waist-hip ratio between the two groups. Total plasma cholesterol, triglyceride and LDL-cholesterol levels were significantly higher and HDL-cholesterol significantly lower in patients as compared to controls. In patients of coronary artery disease, mean lipoprotein(a) levels, measured by ELISA method, were 35.0 +/- 32.4 mg/dL and the median was 26.7 mg/dL. These values were significantly higher than the mean of 20.3 +/- 17.0 mg/dL (p < 0.002) and the median of 13.8 mg/dL (p < 0.015) in controls. Multiple regression analysis, to assess the influence of various risk factors, showed that low HDL-cholesterol (odds ratio 4.62, 95% CI 1.84-11.60; p < 0.015) and elevated lipoprotein(a) levels (odds ratio 3.06, 95% CI 1.24-7.55; p < 0.001) were independent risk factors, whereas high total cholesterol and triglyceride levels did not have any independent influence on premature coronary artery disease. Our data thus suggest that lipoprotein (a) levels are elevated and constitute an independent risk factor in patients with premature coronary artery disease below 40 years of age.     

Transradial primary angioplasty and stenting in Indian patients with acute myocardial infarction: acute results and 6-month follow-up

BACKGROUND: Coronary angioplasty and stent implantation is effective as primary intervention in acute myocardial infarction. Because of fewer puncture site complications and improved patient comfort, transradial access has been increasingly used as an alternative to transfemoral access for percutaneous coronary interventions. METHODS AND RESULTS: We studied 103 patients (94 men, 9 women: mean age 52.5 +/- 11.96 years) with a diagnosis of acute myocardial infarction (<12 hours after onset), who underwent primary percutaneous coronary intervention. Transradial access was used in all patients with a normal Allen's test and transfemoral access was used additionally only if intra-aortic balloon counterpulsation was required. Follow-up duration was 6 months. Transradial access was successfully achieved in all patients. Radial artery cannulation took <2 min in more than 85% patients. During percutaneous coronary intervention, cannulation to balloon inflation times and total procedure times were 11.3 +/- 5.2 min and 19.9 +/- 10.8 min, respectively. Stents were implanted in 99 (96.1%) patients andplain balloon angioplastywas performed in 3.9%. The primary success rate was 98.1%, with no major bleeding complications. Total length of hospitalization averaged 2.4 +/- 0.8 days. In-hospital major adverse clinical events rate was 5.9%. Six-month clinical follow-up was achieved for 84 (86.6%) patients. Six (7.1%) patients died during follow-up. Follow-up coronary angiography was performed in 22 (26.2%) patients. After 6 months, 7 patients required revascularizationof the target lesion. The rate of survival without myocardial infarction, bypass surgery or repeat coronary angioplasty was 88.5% at 6 months. CONCLUSIONS: Transradial access may represent a safe and feasible technique for performing primary percutaneous coronary intervention with good acute results and without major bleeding complications.     

Morbidity compression or expansion? A temporal analysis of the age at onset of non-communicable diseases in India

While there is evidence of morbidity compression in many countries, temporal patterns of non-communicable diseases (NCDs) in developing countries, such as India, are less clear. Age at onset of disease offers insights to understanding epidemiologic trends and is a key input for public health programs. Changes in age at onset and duration of major NCDs were estimated for 2004 (n = 38,044) and 2018 (n = 43,239) using health surveys from the India National Sample Survey (NSS). Survival regression models were used to compare trends by sociodemographic characteristics. Comparing 2004 to 2018, there were reductions in age at onset and increases in duration for overall and cause-specific NCDs. Median age at onset decreased for NCDs overall (57 to 53 years) and for diabetes, hypertension, heart disease, asthma, mental diseases, eye disease, and bone disease in the range of 2–7 years and increased for cancer, neurological disorders, some genitourinary disorders, and injuries/accidents in the range of 2–14 years. Hazards of NCDs were higher among females for cancers (HR 1.51, 95% CI 1.19–1.90) and neurological disorders (HR 1.18, 95% CI 1.06–1.32) but lower for heart diseases (HR 0.88, 95% CI 0.79–0.97) and injuries/accidents (HR 0.87, 95% CI 0.77–0.99). Hazards were greater among those with lower educational attainment at younger ages and higher educational attainment later in life. Unlike many countries, chronic disease morbidity may be expanding in India for many chronic diseases, indicating excess strain on the health system. Public health programs should focus on early diagnosis and prevention of NCDs.

     

Is 30-Day Mortality after Admission for Heart Failure an Appropriate Metric for Quality?

Background

The Centers for Medicare and Medicaid Services (CMS) model for publicly reporting national 30-day-risk-adjusted mortality rates for patients admitted with heart failure fails to include clinical variables known to impact total mortality or take into consideration the culture of end-of-life care. We sought to determine if those variables were related to the 30-day mortality of heart failure patients at Geisinger Medical Center.

Undernutrition among infants less than 6 months of age: an underestimated public health problem in India

In India most childhood nutrition recommendations and interventions are still not focused on infants under 6 months. Secondary data analyses of National Family Health Survey‐3 data from India were analysed to compare the prevalence of wasting, stunting and underweight in infants less than 6 months and 6–59 months. Our results revealed that wasting was higher (31%) in infants less than 6 months (P < 0.05) as compared with children between 6 and 59 months. Thirteen per cent of infants less than 6 months had severe wasting, 30% were underweight and 20% were stunted. Most infants (69%) were exclusively breastfed (EB) for the first 2 months, but exclusive breastfeeding dropped to 50% at 2–3 months and to 27% at 4–5 months. There was no statistically significant difference in wasting and stunting in the EB and not exclusively breastfed (NEB) groups. Significantly fewer EB infants were underweight (28%) compared with NEB infants (31%) (P = 0.030). However, among EB children, 29% had wasting and 21% were stunted. Eleven per cent of EB infants were severely underweight, 13% were severely wasted and 9% were severely stunted. Diarrhoea was significantly lower among EB infants compared with NEB infants (P < 0.05). We conclude that infants less than 6 months of age are vulnerable to suffer from acute severe malnutrition irrespective of their breastfeeding status and need to be seriously considered for inclusion in national guidelines for early detection and management of undernutrition.     

Sleep disorders in pregnancy

PURPOSE OF REVIEW: Sleep disturbances are frequent during pregnancy. The spectrum of association between pregnancy and sleep disturbances ranges from an increased incidence of insomnia, nocturnal awakenings, and parasomnias (especially restless legs syndrome) to snoring and excessive sleepiness. These disturbances occur as a result of physiologic, hormonal, and physical changes associated with pregnancy. Although the timing and occurrence of different sleep disorders varies, they are most prevalent during the third trimester. Despite reports of the various sleep problems, the exact nature and incidence of sleep disorders in pregnancy is not known. Given that limitation, we are presenting an up-to-date review of the current understanding of the relation between sleep and pregnancy. RECENT FINDINGS: Studies suggest that pregnancy affects sleep in multiple ways. There are hormonal changes, physiologic changes, physical factors, and behavioral changes in a pregnant woman-all of which may affect her sleep. They may affect the duration and quality of sleep and lead to a variety of sleep disorders. Pregnancy may also affect an existing sleep disorder. Particular attention may be given to obese pregnant women who would gain more weight during pregnancy or those who develop hypertensive conditions (eg, preeclampsia). Snoring may be more common in women with preeclampsia and the pressor responses to obstructive respiratory events during sleep may be enhanced in preeclamptic women when compared with those with obstructive sleep apnea alone. Several investigators have suggested that obstructive sleep apnea (OSA) may be common in pregnant women despite the presence of intrinsic mechanisms that seem to be geared towards preventing sleep apnea. However, the exact incidence and prevalence of sleep apnea in pregnant women is uncertain. In addition, it is unclear if criteria that are used to define sleep apnea in the general population should be applied to pregnant women. Further investigations are needed to determine if lower thresholds for management of OSA should be used in pregnant women to prevent harm to the fetus. SUMMARY: In conclusion, sleep disturbances are common during pregnancy though the full extent of this relation remains undefined. Large, multi-center, prospective studies are needed for better understanding.     

Effect of losartan in aging-related endothelial impairment

Aging is associated with progressive deterioration in endothelial function. We hypothesized that losartan may represent a useful therapeutic strategy to ameliorate endothelial function in aged subjects. Eighteen healthy older subjects (mean age 75 +/- 3 years) were prospectively randomized in a double-blind, crossover fashion to receive either losartan 50 mg/day or placebo for 6 weeks. Subjects were switched to the opposite arm after a 2- week washout period. Flow-mediated dilation (FMD) in the brachial artery and plasma levels of vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM), moncocyte chemoattractant 1 protein, and E-selectin were measured in both arms at the beginning and end of the 6-week period. Losartan resulted in a 6-mm Hg decrease in systolic blood pressure (from 130 +/- 12 to 124 +/- 13 mm Hg), which was no different from placebo (132 +/- 12 to 127 +/- 13 mm Hg). FMD increased from 3.1 +/- 0.6% to 3.9 +/- 0.6% after losartan, and decreased from 3.3 +/- 0.3% to 2.4 +/- 0.6% after placebo (p = NS for both). In contrast, losartan reduced circulating concentrations of vascular cell adhesion molecule 1 (750 +/- 73 to 572 +/- 39), ICAM (405 +/- 26 to 196 +/- 10), and moncocyte chemoattractant 1 protein (560 +/- 56 to 423 +/- 35) (p <0.01 for all by analysis of variance), but not E-selectin. On univariate analyses, the strongest predictor of baseline endothelial function and change in FMD with losartan was low-density lipoprotein. There was a negative correlation between baseline endothelial function and change in FMD in response to losartan (r(2) = -0.75, p = 0.0003). Baseline ICAM levels alone significantly correlated with low-density lipoprotein cholesterol (r(2) = 0.54, p = 0.02) and weakly correlated with total cholesterol (r(2) = 0.47, p = 0.05). Thus, administration of losartan for a duration of 6 weeks has favorable effects on inflammatory markers in healthy older subjects, but does not alter peripheral conduit endothelial function.     

Bacterial genome reduction using the progressive clustering of deletions via yeast sexual cycling

The availability of genetically tractable organisms with simple genomes is critical for the rapid, systems-level understanding of basic biological processes. Mycoplasma bacteria, with the smallest known genomes among free-living cellular organisms, are ideal models for this purpose, but the natural versions of these cells have genome complexities still too great to offer a comprehensive view of a fundamental life form. Here we describe an efficient method for reducing genomes from these organisms by identifying individually deletable regions using transposon mutagenesis and progressively clustering deleted genomic segments using meiotic recombination between the bacterial genomes harbored in yeast. Mycoplasmal genomes subjected to this process and transplanted into recipient cells yielded two mycoplasma strains. The first simultaneously lacked eight singly deletable regions of the genome, representing a total of 91 genes and ∼10% of the original genome. The second strain lacked seven of the eight regions, representing 84 genes. Growth assay data revealed an absence of genetic interactions among the 91 genes under tested conditions. Despite predicted effects of the deletions on sugar metabolism and the proteome, growth rates were unaffected by the gene deletions in the seven-deletion strain. These results support the feasibility of using single-gene disruption data to design and construct viable genomes lacking multiple genes, paving the way toward genome minimization. The progressive clustering method is expected to be effective for the reorganization of any mega-sized DNA molecules cloned in yeast, facilitating the construction of designer genomes in microbes as well as genomic fragments for genetic engineering of higher eukaryotes.Complexities of natural biological systems make it difficult to understand and define precisely the roles of individual genes and their integrated functions. The use of model organisms with a relatively small number of genes enables the isolation of core biological processes from their complex regulatory networks for extensive characterization. However, even the simplest natural microbes contain many genes of unknown function, as well as genes that can be singly or simultaneously deleted without any noticeable effect on growth rate in a laboratory setting (Hutchison et al. 1999; Glass et al. 2006; Posfai et al. 2006). Ill-defined genes and those mediating functional redundancies both compound the challenge of understanding even the simplest life forms.Toward generating a minimal cell where every gene is essential for the axenic viability of the organism, we are pursuing strategies to reduce the 1-Mb genome of Mycoplasma mycoides JCVI-syn1.0 (Gibson et al. 2010). Because we can (1) introduce this genome into yeast and maintain it as a plasmid (Benders et al. 2010; Karas et al. 2013a); and (2) “transplant” the genome from yeast into mycoplasma recipient cells (Lartigue et al. 2009), genetic tools in yeast are available for reducing this bacterial genome. Several systems offer advanced tools for bacterial genome engineering. Here we further exploit distinctive features of yeast for this purpose.Methods for serially replacing genomic regions with selectable markers are limited by the number of available markers. One effective approach is to reuse the same marker after precise and scarless marker excision (Storici et al. 2001). We have previously used a self-excising marker (Noskov et al. 2010) six times in yeast to generate a JCVI-syn1.0 genome lacking all six restriction systems (JCVI-syn1.0 ∆1-6) (Karas et al. 2013a). Despite the advantages of scarless engineering, sequential procedures are time-consuming. When applied to poorly characterized genes with the potential to interact with other genes, some paths for multigene knockout may lead to dead ends that result from synergistic mutant phenotypes. When a dead end is reached, sequentially returning to a previous genome in an effort to find a detour to a viable higher-order multimutant may be prohibitively time-consuming.An alternative approach to multigene engineering, available in yeast, is to prepare a set of single mutants and combine the deletions into a single strain via cycles of mating and meiotic recombination (Fig. 1A; Pinel et al. 2011; Suzuki et al. 2011, 2012). With a green fluorescent protein (GFP) reporter gene inserted in each deletion locus, the enrichment of higher-order yeast deletion strains in the meiotic population can be accomplished using flow cytometry. Here we apply this method to the JCVI-syn1.0 ∆1-6 exogenous, bacterial genome harbored in yeast to nonsequentially assemble deletions for genes predicted to be individually deletable based on biological knowledge or transposon-mediated disruption data. The functional identification of simultaneously deletable regions is expected to accelerate the effort to construct a minimal genome.Open in a separate windowFigure 1.Progressive clustering of deleted genomic segments. (A) Scheme of the method. Light blue oval represents a bacterial cell. Black ring or horizontal line denotes a bacterial genome, with the orange box indicating the yeast vector used as a site for linearization and recircularization. Gray shape denotes a yeast cell. Green dot in the genome indicates a deletion replaced with a GFP marker. (B) Map of deleted regions. Orange box indicates the yeast vector sequence used for genome linearization and recircularization. Green boxes indicate regions deleted in multimutant mycoplasma strains. Blue boxes denote restriction modification (RM) systems that are also deleted in the strains. (C) Pulsed-gel electrophoresis result for deleted genomes. The starting strain was the JCVI-syn1.0 ∆1–6 strain (1062 kb). Two strains were analyzed for each design of simultaneous deletion (962 kb for eight-deletion or 974 kb for seven-deletion genome). Ladder is a set of yeast chromosomes (New England BioLabs). (D) GFP-RFP ratio sorting result. Standard sorting was compared with sorting based on a GFP-RFP ratio (Methods).